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Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion
Author(s) -
Baba Takashi,
Toth Daniel J,
Sengupta Nivedita,
Kim Yeun Ju,
Balla Tamas
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100312
Subject(s) - human development (humanity) , child health , library science , psychology , chemistry , political science , medicine , family medicine , law , computer science
The small GTP ase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP / GTP ‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI 4P, which is primarily produced by PI 4K2A kinase. Acute conversion of this endosomal PI 4P to PI (4,5)P 2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM 1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI (4,5)P 2 production. Deletion of PI 4K2A greatly reduces PIP 5Kγ‐mediated PI (4,5)P 2 production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC 3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI 4P‐ PI (4,5)P 2 ‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM 1 association.